Process for the preparation of 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid esters

ABSTRACT

The present invention provides a method of producing 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester (VII) economically, industrially advantageously and efficiently in a large amount. The present invention relates to a production method of compound (VII), which includes reacting epoxide (I) with amine (II) to give aminodiol (III), reacting the aminodiol (III) with a sulfonylating agent in the presence of a base to give azabicyclohept-2-ene (IV), reacting the azabicyclohept-2-ene (IV) with alcohol (V) in the presence of a Lewis acid to give azabicyclohept-3-ene (VI), and eliminating the 7-position substituent R 2  from the azabicyclohept-3-ene (VI)

TECHNICAL FIELD

The present invention relates to a production method of7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester.7-Azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester, such as ethyl(1α,5α,6α)-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate,obtained by the present invention, is useful as a synthetic intermediatefor GS4104 represented by the following formula. GS4104 is a compoundunder development as a novel agent for the prophylaxis and treatment ofinfluenza based on the action to prevent viral growth by inhibitingneuraminidase present on the surface of influenza virus (hereinafter tobe generally referred to as anti-influenza drug) [see Journal of OrganicChemistry (J. Org. Chem.), vol. 63, p. 4545 (1998); Journal of AmericanChemical Society (J. Am. Chem. Soc.), vol. 119, p. 681 (1997)].

BACKGROUND ART

As a conventional synthetic method of7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester, such as ethyl(1α,5α,6α)-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate,a synthetic method wherein shikimic acid is used as a starting material[see Journal of Organic Chemistry (J. Org. Chem.), vol. 63, p. 4545(1998); WO 99/14185; WO 98/07685], and a synthetic method wherein guinicacid is used as a starting material [see Journal of American ChemicalSociety (J. Am. Chem. Soc.), vol. 119, p. 681 (1997)] and the like areknown.

The shikimic acid and quinic acid used as a starting material for theconventional synthetic method of ethyl(1α,5α,6α)-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylateare produced in less amounts and expensive. All the above-mentionedmethods require many reaction steps. As widely known, influenza oftenbecomes an epidemic disease worldwide, and an anti-influenza drug isrequired to be economical and supplied in a large amount. Theabove-mentioned production methods are not necessarily advantageous as aproduction method of the intermediate for GS4104 under development as ananti-influenza drug from the industrial viewpoint, and there is a demandfor a synthetic method capable of economical production in a largeamount.

DISCLOSURE OF INVENTION

It is therefore an object of the present invention to provide aproduction method of a 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acidester, such as ethyl(1α,5α,6α)-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate,useful as a synthetic intermediate for GS4104 under development as ananti-influenza drug, economically, industrially advantageously andefficiently in a large amount.

According to the present invention, the above-mentioned objects can beachieved by providing

1) a production method of a 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylicacid ester of the formula (VII)

wherein R¹ is an alkyl group optionally having substituents, acycloalkyl group optionally having substituents, an aryl groupoptionally having substituents or an aralkyl group optionally havingsubstituents and R³ is an alkyl group optionally having substituents, acycloalkyl group optionally having substituents, an alkenyl groupoptionally having substituents, an aryl group optionally havingsubstituents or an aralkyl group optionally having substituents[hereinafter to be abbreviated as7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester (VII)], whichcomprises the steps of

(A) reacting a 5-hydroxy-7-oxabicyclo[4.1.0]hept-2-ene-3-carboxylic acidester of the formula (I)

wherein R¹ is as defined above [hereinafter to be abbreviated as epoxide(I)] with an amine of the formula (II)

R²NH₂  (II)

wherein R² is a hydrogen atom, an alkyl group optionally havingsubstituents, a cycloalkyl group optionally having substituents, analkenyl group optionally having substituents, an aryl group optionallyhaving substituents or an aralkyl group optionally having substituents[hereinafter to be abbreviated as amine (II)] to give a3-amino-4,5-dihydroxy-1-cyclohexene-1-carboxylic acid ester of theformula (III)

wherein R¹ and R² are as defined above [hereinafter to be abbreviated asaminodiol (III)],

(B) reacting the obtained aminodiol (III) with a sulfonylating agent inthe presence of a base to give a5-sulfonyloxy-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylic acid ester ofthe formula (IV)

wherein R¹ and R² are as defined above and A is an organic sulfonylgroup [hereinafter to be abbreviated as azabicyclohept-2-ene (IV)],

(C) reacting the obtained azabicyclohept-2-ene (IV) with an alcohol ofthe formula (V)

R³OH  (V)

wherein R³ is as defined above [hereinafter to be abbreviated as alcohol(V)] in the presence of a Lewis acid to give a5-oxy-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester of theformula (VI)

wherein R¹, R² and R³ are as defined above [hereinafter to beabbreviated as azabicyclohept-3-ene (VI)], and

(D) when R² is an alkyl group optionally having substituents, acycloalkyl group optionally having substituents, an alkenyl groupoptionally having substituents, an aryl group optionally havingsubstituents or an aralkyl group optionally having substituents,eliminating the 7-position substituent R² of the obtainedazabicyclohept-3-ene (VI),

(2) a production method of a 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylicacid ester (VII), which comprises the steps of

(A) reacting epoxide (I) with amine (II) to give aminodiol (III),

(B) protecting an amino group of the obtained aminodiol (III) to give a3-amino-4,5-dihydroxy-1-cyclohexene-1-carboxylic acid ester of theformula (VIII)

wherein R¹ and R² are as defined above and R⁴ is an amino-protectinggroup [hereinafter to be abbreviated as aminodiol (VIII)],

(C) reacting the obtained aminodiol (VIII) with a sulfonylating agent inthe presence of a base to give a3-amino-4,5-disulfonyloxy-1-cyclohexene-1-carboxylic acid ester of theformula (IX)

wherein R¹, R² and R⁴ are as defined above and A is an organic sulfonylgroup [hereinafter to be abbreviated as disulfonate (IX)],

(D) removing the amino-protecting group from the obtained disulfonate(IX) to give a 3-amino-4,5-disulfonyloxy-1-cyclohexene-1-carboxylic acidester of the formula (X)

wherein R¹, R² and A are as defined above [hereinafter to be abbreviatedas disulfonate (X)],

(E) reacting the obtained disulfonate (X) with a base to giveazabicyclohept-2-ene (IV),

(F) reacting the obtained azabicyclohept-2-ene (IV) with alcohol (V) inthe presence of a Lewis acid to give azabicyclohept-3-ene (VI), and

(G) when R² is an alkyl group optionally having substituents, acycloalkyl group optionally having substituents, an alkenyl groupoptionally having substituents, an aryl group optionally havingsubstituents or an aralkyl group optionally having substituents,eliminating the 7-position substituent R² from the obtainedazabicyclohept-3-ene (VI),

(3) a production method of a 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylicacid ester (VII), which comprises eliminating the 7-position substituentR^(2′), from a 5-oxy-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acidester of the formula (VI′)

wherein R^(2′), is an alkyl group optionally having substituents, acycloalkyl group optionally having substituents, an alkenyl groupoptionally having substituents, an aryl group optionally havingsubstituents or an aralkyl group optionally having substituents, and R¹and R³ are as defined above,

(4) a production method of azabicyclohept-3-ene (VI), which comprisesreacting azabicyclohept-2-ene (IV) with alcohol (V) in the presence of aLewis acid,

(5) a production method of azabicyclohept-2-ene (IV), which comprisesreacting aminodiol (III) with a sulfonylating agent in the presence-of abase,

(6) a production method of azabicyclohept-2-ene (IV), which comprisesreacting disulfonate (X) with a base,

(7) a production method of azabicyclohept-2-ene (IV), which comprises(A) protecting an amino group of aminodiol (III) to give aminodiol(VIII),

(B) reacting the obtained aminodiol (VIII) with a sulfonylating agent inthe presence of a base to give disulfonate (IX),

(C) removing the amino-protecting group of the obtained disulfonate (IX)to give disulfonate (X), and

(D) reacting the obtained disulfonate (X) with a base, and

(8) a production method of aminodiol (III), which comprises reactingepoxide (I) with amine (II).

In the above-mentioned formulas, the alkyl group represented by R¹, R²and R³ is a straight chain or branched chain alkyl group preferablyhaving 1 to 10, more preferably 1 to 6 carbon atoms. Examples thereofinclude methyl group, ethyl group, propyl group, isopropyl group,n-butyl group, isobutyl group, tert-butyl group, pentyl group,1-ethylpropyl group, hexyl group and the like. These alkyl groups mayhave substituents and examples of the substituent include alkoxyl grouppreferably having 1 to 10, more preferably 1 to 6 carbon atoms, such asmethoxy group, ethoxy group, propoxy group, butoxy group and the like;halogen atom such as fluorine atom, chlorine atom, bromine atom and thelike; cyano group; nitro group; and the like.

The cycloalkyl group represented by R¹, R² and R³ is cycloalkyl grouppreferably having 3 to 8 carbon atoms and is exemplified by cyclopentylgroup, cyclohexyl group, cyclooctyl group and the like. The aryl grouprepresented by R¹, R² and R³ is aryl group preferably having 6 to 10carbon atoms, and is exemplified by phenyl group, naphthyl group and thelike. The aralkyl group represented by R¹, R² and R³ is aralkyl groupwherein the alkyl moiety is alkyl group preferably having 1 to 6 carbonatoms and the aryl moiety has 1 to 3 aryl groups defined above. Examplesthereof include benzyl group, diphenylmethyl group, triphenylmethylgroup, phenethyl group and the like. These cycloalkyl group, aryl groupand aralkyl group may have substituents and examples of the substituentinclude alkyl group preferably having 1 to 6 carbon atoms such as methylgroup, ethyl group, propyl group, isopropyl group, n-butyl group,isobutyl group, tert-butyl group and the like; alkoxyl group preferablyhaving 1 to 6 carbon atoms such as methoxy group, ethoxy group, propoxygroup, butoxy group and the like; halogen atom such as fluorine atom,chlorine atom bromine atom and the like; cyano group; nitro group andthe like.

The alkenyl group represented by R² and R³ is a straight chain orbranched chain alkenyl group preferably having 2 to 10, more preferably2 to 6 carbon atoms. Examples thereof include allyl group, isopropenylgroup, 2-methylallyl group and the like. These alkenyl groups may havesubstituents and examples of the substituent include alkoxyl grouppreferably having 1 to 6 carbon atoms such as methoxy group, ethoxygroup, propoxy group, butoxy group and the like; halogen atom such asfluorine atom, chlorine atom, bromine atom and the like; cyano group;nitro group; and the like.

As R², an aralkyl group optionally having substituents (e.g., benzylgroup, diphenylmethyl group) is preferable.

The protecting group of the amino group represented by R⁴ is free of anyparticular limitation as long as it is generally used for protecting theamino group, and is exemplified by alkoxycarbonyl group such astert-butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group,2-iodoethoxycarbonyl group, 2-trimethylsilylethoxycarbonyl group,2-methylthioethoxycarbonyl group, 1,1-dimethylpropyloxycarbonyl group,1-methyl-1-phenylethoxycarbonyl group, vinyloxycarbonyl group,allyloxycarbonyl group, cinnamyloxycarbonyl group,1,1-dimethylpropynyloxycarbonyl group and the like; aralkyloxycarbonylgroup such as 9-fluorenylmethoxycarbonyl group, benzyloxycarbonyl group,p-methoxybenzyloxycarbonyl group, 3,5-dimethoxybenzyloxycarbonyl group,p-nitrobenzyloxycarbonyl group, o-nitrobenzyloxycarbonyl group and thelike; aralkyl group such as benzyl group, 2,4,6-trimethylbenzyl group,p-methoxybenzyl group, 3,5-dimethoxybenzyl group, p-nitrobenzyl group,o-nitrobenzyl group, o-chlorobenzyl group, p-chlorobenzyl group,o-bromobenzyl group, p-bromobenzyl group, 2,4-dichlorobenzyl group,p-cyanobenzyl group, m-chloro-p-acyloxybenzyl group, 9-anthrylmethylgroup, diphenylmethyl group, phenyl(o-nitrophenyl)methyl group,di(2-pyridyl)methyl group, (4-pyridyl)methyl group, triphenylmethylgroup and the like; acyl group such as formyl group, acetyl group,chloroacetyl group, dichloroacetyl group, trichloroacetyl group,trifluoroacetyl group, o-nitrophenylacetyl group, p-nitrophenylacetylgroup, o-nitrophenoxyacetyl group, p-nitrophenoxyacetyl group,acetoacetyl group, pyridylacetyl group and the like; and the like.

The organic sulfonyl group represented by A is free of any particularlimitation as long as it is bonded with an organic group, and isexemplified by alkylsulfonyl group optionally having substituents,arylsulfonyl group optionally having substituents, aralkylsulfonyl groupoptionally having substituents and the like. The alkyl moiety of thealkylsulfonyl group is alkyl group preferably having 1 to 6 carbonatoms. The aryl moiety of the arylsulfonyl group is, for example, phenylgroup. The aryl moiety of the aralkylsulfonyl group is, for example,phenyl group, and the alkyl moiety is alkyl group preferably having 1 to6 carbon atoms. The alkylsulfonyl group may have substituents, andexamples of the substituent include alkoxyl group (alkoxyl grouppreferably having 1 to 6 carbon atoms), halogen atom, cyano group, nitrogroup and the like. The arylsulfonyl group and aralkylsulfonyl group mayhave substituents on the aromatic ring, and examples of the substituentinclude alkyl group (alkyl group preferably having 1 to 6 carbon atoms),alkoxyl group (alkoxyl group preferably having 1 to 6 carbon atoms),halogen atom, cyano group, nitro group and the like. The organicsulfonyl group represented by A is exemplified by methanesulfonyl group,ethanesulfonyl group, benzenesulfonyl group, toluenesulfonyl group,p-methoxybenzenesulfonyl group, 2,4,6-trimethylbenzenesulfonyl group,benzylsulfonyl group, p-methylbenzylsulfonyl group,trifluoromethanesulfonyl group and the like.

The production method of 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acidester (VII) of the present invention is shown in the following scheme,and includes two production methods of route (i) and route (ii), whichcan be determined as appropriate according to the kind of amine (II) tobe used.

wherein R¹, R², R³, R⁴ and A are as defined above.

In the following, each step is explained.

(a): step for reacting epoxide (I) with amine (II) to give aminodiol(III)

Examples of the amine (II) include ammonia, methylamine, ethylamine,propylamine, n-butylamine, cyclohexylamine, cyclooctylamine, allylamine,isopropenylamine, aniline, 4-methylphenylamine, benzylamine,benzhydrylamine and the like. Of these, benzylamine and benzhydrylamineare particularly preferable. The amount of the amine (II) to be used isgenerally preferably 1 to 10-fold moles, particularly preferably 1 to1.5-fold moles, per 1 mole of epoxide (I).

The reaction can be carried out in the presence or absence of a solvent.The solvent to be used is free of any particular limitation as long asit does not adversely affect the reaction. Examples thereof includealiphatic hydrocarbon such as hexane, heptane, octane and the like;aromatic hydrocarbon such as benzene, toluene, xylene, mesitylene andthe like; ether such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane and the like; and the like. When a solvent isused, the amount of the solvent to be used is free of any particularlimitation, but it is generally preferably 1 to 10-fold weight, morepreferably 1 to 3-fold weight, relative to epoxide (I).

The reaction temperature is preferably 20 to 200° C., more preferably50° C. to 80° C. While the reaction time varies depending on the kindand the amount of epoxide (I), amine (II) and the solvent, it isgenerally within the range of 1 to 48 hours.

The reaction is carried out by, for example, mixing epoxide (I), amine(II) and a solvent as necessary and stirring the mixture at a giventemperature.

The aminodiol (III) thus obtained can be purified and separatedaccording to a method generally employed for the purification andseparation of organic compounds. For example, the reaction mixture isconcentrated, and the obtained concentrate is purified by distillation,column chromatography and the like.

(b): Step for reacting aminodiol (III) with a sulfonylating agent in thepresence of a base to give azabicyclohept-2-ene (IV)

Examples of the base include tertiary amine such as trimethylamine,triethylamine, tripropylamine, tributylamine, trioctylamine, pyridine,collidine, lutidine and the like; alkaline metal hydride such as sodiumhydride, potassium hydride and the like; alkaline metal carbonate suchas sodium carbonate, potassium carbonate and the like; and the like. Ofthese, triethylamine, pyridine and lutidine are preferable. The amountof the base to be used is preferably 2 to 100-fold moles, morepreferably 2 to 25-fold moles, per 1 mole of aminodiol (III).

Examples of the sulfonylating agent include organic sulfonyl halide suchas methanesulfonyl chloride, methanesulfonyl fluoride, ethanesulfonylchloride, ethanesulfonyl bromide, benzenesulfonyl chloride,benzenesulfonyl bromide, benzenesulfonyl fluoride, toluenesulfonylchloride, toluenesulfonyl bromide, toluenesulfonyl fluoride,p-methoxybenzenesulfonyl chloride, 2,4,6-trimethylbenzenesulfonylchloride, benzylsulfonyl chloride, p-methylbenzylsulfonyl chloride,trifluoromethanesulfonyl chloride and-the like; sulfonic anhydride suchas methanesulfonic anhydride, p-toluenesulfonic anhydride,trifluoromethanesulfonic anhydride and the like; and the like. Theamount of the sulfonylating agent to be used is preferably 2 to 10-foldmoles, more preferably 2 to 5-fold moles, per 1 mole of aminodiol (III).

The reaction is preferably carried out in a solvent. The solvent to beused is free of any particular limitation as long as it does notadversely affect the reaction. Examples thereof include aliphatichydrocarbon such as hexane, heptane, octane and the like; aromatichydrocarbon such as benzene, toluene, xylene, mesitylene and the like;ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxaneand the like; halogenated hydrocarbon such as dichloromethane,chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; andthe like. The amount of the solvent to be used is free of any particularlimitation, but it is generally preferably 1 to 100-fold weight, morepreferably 1 to 10-fold weight, relative to aminodiol (III).

The reaction temperature is preferably −20° C. to 1500° C., morepreferably 10° C. to 80° C. While the reaction time varies depending onthe kind and the amount of aminodiol (III), base, sulfonylating agentand solvent, it is generally within the range of 1 to 48 hours.

The reaction is carried out by, for example, dissolving aminodiol (III)and a base in a solvent, adding a sulfonylating agent and stirring themixture at a given temperature.

The azabicyclohept-2-ene (IV) thus obtained can be purified andseparated according to a method generally employed for the purificationand separation of organic compounds. For example, the reaction mixtureis poured into water, extracted with aliphatic hydrocarbon such asn-hexane and the like, aromatic hydrocarbon such as toluene and thelike, halogenated hydrocarbon such as dichloromethane and the like,ether such as diethyl ether, diisopropyl ether and the like; and thelike, and the extract is concentrated and the obtained concentrate ispurified by distillation, column chromatography and the like.

(c): step for reacting azabicyclohept-2-ene (IV) and alcohol (V) in thepresence of Lewis acid to-give azabicyclohept-3-ene (VI)

Examples of the alcohol (V) include primary alcohol such as methanol,ethanol, 1-propanol, 1-octanol, allyl alcohol, benzyl alcohol and thelike; secondary alcohol such as isopropanol, 2-butanol, 3-pentanol,cyclopentanol, cyclohexanol and the like. Of these, the use of3-pentanol as alcohol (V) is particularly preferable from the viewpointof synthesis of ethyl(1α,5α,6α)-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate,which is a synthetic intermediate for GS4104. The amount of the alcohol(V) to be used is preferably 1 to 200-fold moles, more preferably 10 to100-fold moles, per 1 mole of azabicyclohept-2-ene (IV).

Examples of the Lewis acid include boron trifluoride-etherate, aluminumchloride, zinc chloride, zinc iodide, titanium tetrachloride and thelike. The amount of the Lewis acid to be used is preferably 0.1 to30-fold moles, more preferably 1 to 10-fold moles, per 1 mole ofazabicyclohept-2-ene (IV).

The reaction can be carried out in the presence or absence of a solvent.Examples of the solvent to be used is free of any particular limitationas long as it does not adversely affect the reaction. Examples of thesolvent include aliphatic hydrocarbon such as hexane, heptane, octaneand the like; aromatic hydrocarbon such as benzene, toluene, xylene,mesitylene and the like; ether such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane and the like; halogenated hydrocarbon such asdichloromethane, chloroform, carbon tetrachloride, -1,2-dichloroethaneand the like; and the like. When a solvent is used, the amount thereofis free of any particular limitation. It is generally preferably 1 to100-fold weight, more preferably 1 to 10-fold weight relative toazabicyclohept-2-ene (IV).

For efficient progress of the reaction, a base may be also presentduring the reaction. Examples of the base include amine such astriethylamine, pyridine, collidine, lutidine and the like; alkalinemetal hydride such as sodium hydride, potassium hydride and the like;alkaline metal carbonate such as sodium carbonate, potassium carbonateand the like; and the like. When a base is co-used, the amount thereofis free of any particular limitation, but it is preferably 2 to 100-foldmoles, more preferably 2 to 25-fold moles, relative toazabicyclohept-2-ene (IV). 10 The reaction temperature is preferably0-100° C., more preferably 10-80° C. While the reaction time variesdepending on the kind and the amount of azabicyclohept-2-ene (IV),alcohol (V), Lewis acid and solvent, it is generally 0.5 to 10 hours.

The reaction is carried out by, for example, mixing azabicyclohept-2-ene(IV), alcohol (V), Lewis acid and a solvent as necessary and stirringthe mixture at a given temperature. When a base is further co-used forthe reaction, the base is preferably added after start of stirring asmentioned above. In this case, the given amount of the base may be addedat once or added by several-divided portions.

The azabicyclohept-3-ene (VI) thus obtained can be purified andseparated according to a method generally employed for the purificationand separation of organic compounds. For example, the reaction mixtureis poured into water, extracted with aliphatic hydrocarbon such asn-hexane and the like, aromatic hydrocarbon such as toluene and thelike, ether such as diethyl ether, diisopropyl ether and the like; andthe like, and the extract is concentrated and the obtained concentrateis purified by distillation, column chromatography and the like.

When R² is a hydrogen atom, the objective7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester (VII) can beobtained at this stage without performing the next step (d).

(d): step for obtaining 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acidester (VII) by eliminating the 7-position substituent R² fromazabicyclohept-2-ene (VI) The 7-position substituent R² can beeliminated from azabicyclohept-3-ene (VI) by, for example, a treatmentwith an acid or according to a known method using catalytichydrogenation (T. W. Green, “Protective Groups in organic Synthesis,”John-Wiley & Sons, New York, pp 218-287 (1981)).

For the treatment with an acid, azabicyclohept-3-ene (VI) is broughtinto contact with, for example, a solution of hydrogen chloride orhydrogen bromide in alcohol such as ethanol and the like. Examples ofthe catalytic hydrogenation include a method including reactingazabicyclohept-3-ene (VI) with a hydrogen source such as hydrogen,formic acid and the like in the presence of a catalyst such asRaney-nickel, palladium-carbon and the like.

Particularly, when the 7-position substituent R² is an aralkyl group,such as benzyl group and diphenylmethyl group, a method for eliminatingthe 7-position substituent using palladium-carbon as a catalyst andformic acid as a hydrogen source is particularly preferable, becauseonly the 7-position substituent can be selectively eliminated withoutreducing the double bond of cyclohexene ring. The palladium-carbon to beused here may be those commercially available for hydrogenation, whereno limitation is imposed on the amount of palladium to be carried andthe like. The weight of palladium-carbon to be used is preferably 0.1 to10-fold weight, more preferably 0.5 to 3-fold weight, relative toazabicyclohept-3-ene (VI). The amount of the formic acid to be used ispreferably 1 to 100-fold moles, more preferably 1 to 10-fold moles,relative to azabicyclohept-3-ene (VI). The reaction is preferablycarried out in a solvent. As the solvent, alcohol such as methanol,ethanol and the like; aliphatic hydrocarbon such as hexane, heptane,octane and the like; ether such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane and the like; aromatic hydrocarbon such asbenzene, toluene, xylene, mesitylene and the like; halogenatedhydrocarbon such as dichloromethane, chloroform, carbon tetrachloride,1,2-dichloroethane and the like; and the like are exemplified. Of these,aliphatic hydrocarbon such as hexane, heptane, octane and the like;alcohol such as methanol, ethanol and the like are more preferable. Theamount of the solvent to be used is free of any particular limitationbut it is generally preferably 1 to 100-fold weight, more preferably 1to 10-fold weight, relative to azabicyclohept-3-ene (VI). The reactiontemperature is preferably −50 to 100° C., more preferably −20 to 50° C.

The 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester (VII) thusobtained can be purified and separated according to a method generallyemployed for the purification and separation of organic compounds. Forexample, the reaction mixture is neutralized or filtrated, thenconcentrated, and the obtained concentrate is purified by distillation,column chromatography and the like.

(e): step to protect amino group of aminodiol (III) to give aminodiol(VIII)

As the protecting group used to protect amino group of aminodiol (III),the protecting groups generally used for the protection of amino groupcan be used. Of these protecting groups, those stable under the reactionconditions, under which to produce disulfonate (IX) in the next step(f), and capable of being removed when the protecting group is to bequickly removed in step (g) to be mentioned below, without impairingother moieties of disulfonate (X) are particularly preferable. Examplesof the amino-protecting group include alkoxycarbonyl group such astert-butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group,1,1-dimethylpropyloxycarbonyl group and the like; aralkyloxycarbonylgroup such as p-methoxybenzyloxycarbonyl group and the like. Of these,tert-butoxycarbonyl group is particularly preferable. Theseamino-protecting groups can be introduced by a known method (T. W.Green, “Protective Groups in Organic Synthesis,” John-Wiley & Sons, NewYork, pp 218-287 (1981)). For example, tert-butoxycarbonyl group can beintroduced by the use of di-tert-butyl dicarbonate in an amount of 1 to3-fold moles, more preferably 1 to 1.2-fold moles, relative to-aminodiol(III).

The reaction to protect amino group is preferably carried out in thepresence of a solvent. The solvent to be used is free of any particularlimitation as long as it does not adversely affect the reaction andexamples thereof include halogenated hydrocarbon such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; aliphatic hydrocarbon such as hexane, heptane, octane andthe like; aromatic hydrocarbon such as benzene, toluene, xylene,mesitylene and the like; ether such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane and the like; acetonitrile; and the like. Theamount of the solvent to be used is free of any particular limitation,but generally it is preferably 1 to 100-fold weight, more preferably 1to 10-fold weight, relative to aminodiol (III).

The reaction temperature is preferably −20 to 150° C., more preferably20 to 80° C.

The aminodiol (VIII) thus obtained can be purified and separatedaccording to a method generally employed for the purification andseparation of organic compounds. For example, the reaction mixture ispoured into water, extracted with aliphatic hydrocarbon such as n-hexaneand the like, aromatic hydrocarbon such as toluene and the like, ethersuch as diethyl ether, diisopropyl ether and the like; and the like, andthe extract is concentrated and the obtained concentrate is purified bydistillation, column chromatography and the like.

(f): step for reacting aminodiol (VIII) with a sulfonylating agent inthe presence of a base to give disulfonate (IX)

As the sulfonylating agent, the compounds recited in the above-mentionedstep (b) can be used. The amount of the sulfonylating agent to be usedis preferably 2 to 10-fold moles, more preferably 2 to 5-fold moles, per1 mole of aminodiol (VIII).

Examples of the base include tertiary amine such as trimethylamine,triethylamine, tripropylamine, tributylamine, trioctylamine, pyridine,collidine, lutidine and the like; alkaline metal hydride such as sodiumhydride, potassium hydride and the like; alkaline metal carbonate suchas sodium carbonate, potassium carbonate and the like; and the like. Ofthese, triethylamine, pyridine and lutidine are preferable. The amountof the base to be used is preferably 2 to 10-fold moles, more preferably2 to 5-fold moles, per 1 mole of aminodiol (VIII).

The reaction is preferably carried out in the presence of a solvent. Thesolvent to be used is free of any particular limitation as long as it isnot involved in the reaction. Examples thereof include aliphatichydrocarbon such as hexane, heptane, octane and the like; aromatichydrocarbon such as benzene, toluene, xylene, mesitylene and the like;ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxaneand the like; halogenated hydrocarbon such as dichloromethane,chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; andthe like. The amount of the solvent to be used is free of any particularlimitation but it is generally preferably 1 to 100-fold weight, morepreferably 1 to 10-fold weight, relative to aminodiol (VIII).

The reaction temperature is preferably 0-50° C., more preferably 10-30°C. While the reaction time varies depending on the kind and the amountof aminodiol (VIII), base, sulfonylating agent and solvent, it isgenerally 1 to 48 hours.

The reaction is preferably carried out by, for example, dissolvingaminodiol (VIII) and a base in a solvent, adjusting to a giventemperature, adding a sulfonylating agent and stirring the mixture.

The disulfonate (IX) thus obtained can be purified and separatedaccording to a method generally employed for the purification andseparation of organic compounds. For example, the reaction mixture ispoured into water, extracted with aliphatic hydrocarbon such as n-hexaneand the like, aromatic hydrocarbon such as toluene and the like, ethersuch as diethyl ether, diisopropyl ether and the like; and the like, andthe extract is concentrated and the obtained concentrate is purified bydistillation, column chromatography and the like.

(g): step to remove amino-protecting group from disulfonate (IX) to givedisulfonate (X)

The amino-protecting group can be removed from disulfonate (IX)according to a known method (T. W. Green, “Protective Groups in OrganicSynthesis,” John-Wiley & Sons, New York, pp 218-287 (1981)). When theamino-protecting group is tert-butoxycarbonyl group, it can be removedby using trifluoroacetic acid, trimethylbromosilane, trimethyliodosilaneand the like and halogenated hydrocarbon such as dichloromethane,chloroform and the like as a solvent in a proportion of 1 to 100-foldweight, preferably 1 to 10-fold weight, relative to disulfonate (IX), ata reaction temperature of 0-50° C., preferably 10-30° C. The obtaineddisulfonate (X) can be purified and separated according to a methodgenerally employed for the purification and separation of organiccompounds. For example, the reaction mixture is poured into water,extracted with aliphatic hydrocarbon such as n-hexane and the like,aromatic hydrocarbon such as toluene and the like, ether such as diethylether, diisopropyl ether and the like; and the like, and the extract isconcentrated and the obtained concentrate is purified by distillation,column chromatography and the like.

(h): step to react disulfonate (X) with a base to obtainazabicyclohept-2-ene (IV)

Examples of the base include tertiary amine such as trimethylamine,triethylamine, tripropylamine, tributylamine, trioctylamine, pyridine,collidine, lutidine and the like; alkaline metal hydride such as sodiumhydride, potassium hydride and the like; alkaline metal carbonate suchas sodium carbonate, potassium carbonate and the like; and the like. Ofthese, triethylamine, pyridine and lutidine are preferable. The amountof the base to be used is preferably 2 to 100-fold moles, morepreferably 2 to 25-fold moles, per 1 mole of disulfonate (X).

The reaction is preferably carried out in the presence of a solvent. Thesolvent to be used is free of any particular limitation as long as it isnot involved in the reaction. Examples thereof include aliphatichydrocarbon such as hexane, heptane, octane and the like; aromatichydrocarbon such as benzene; toluene, xylene, mesitylene and the like;ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxaneand the like; halogenated hydrocarbon such as dichloromethane,chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; andthe like. The amount of the solvent to be used is free of any particularlimitation, and generally it is preferably 1 to 100-fold weight, morepreferably 1 to 10-fold weight, relative to disulfonate (X).

The reaction temperature is preferably 0-150° C., more preferably 20-80°C. While the reaction time varies depending on the kind and the amountof use of disulfonate (X), base and solvent, it is generally 1 to 48hours.

The reaction is preferably carried out by, for example, dissolvingdisulfonate (X) and a base in a solvent and stirring the mixture at agiven temperature.

The azabicyclohept-2-ene (IV) thus obtained can be purified andseparated according to a method generally employed for the purificationand separation of organic compounds. For example, the reaction mixtureis poured into water, extracted with aliphatic hydrocarbon such asn-hexane and the like, aromatic hydrocarbon such as toluene and thelike, ether such as diethyl ether, diisopropyl ether and the like; andthe like, and the extract is concentrated and the obtained concentrateis purified by distillation, column chromatography and the like.

The epoxide (I), which is a starting material for the present invention,can be produced as shown in Reference Examples 1-3 to be mentionedbelow, wherein furan and acrylic acid ester of the formula (XI)

wherein R¹ is as defined above, are subjected to a Diels-Alder reactionin the presence of Lewis acid, such as zinc iodide, zinc chloride,titanium tetrachloride and the like, the obtained compound is reactedwith a base such as lithium diisopropylamide, lithiumhexamethyldisilazide and the like to perform intramolecularretro-Michael reaction to give dieno alcohol of the formula (XII)

wherein R¹ is as defined above [see Tetrahedron Letters, vol. 23, p.5299 (1982)], and this dieno alcohol is reacted with peroxide such asmagnesium monoperoxyphthalate, peracetic acid, m-chloroperbenzoic acidand the like [see Journal of American Chemical Society (J. Am. Chem.Soc.), vol. 104, p. 7036 (1982)].

According to the method described in Journal of Organic Chemistry (J.Org. Chem.), vol. 63, p. 4545 (1998), GS4104 can be synthesized from7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester (VII), such asethyl(1α,5α,6α)-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylateobtained by the method of the present invention.

EXAMPLE

The present invention is described in more detail by means of thefollowing Examples, which are not to be construed as limitative.

Reference Example 1 Synthesis of2-ethoxycarbonyl-7-oxabicyclo[2.2.1]hept-5-ene

Furan (2.04 ml, 28 mmol), ethyl acrylate (2.06 ml, 20 mmol) and zinciodide (1.92 g, 6 mmol) were placed in a sealed tube and the mixture washeated at 40° C. for 2 days. The reaction mixture was cooled to roomtemperature and diluted with ethyl acetate (100 ml). 10% Aqueous sodiumthiosulfate solution (20 ml) was added, and the mixture was stirred atroom temperature for 30 min. The organic layer was partitioned, washedwith saturated brine (100 ml), and dried over anhydrous sodium sulfate.The components having a low boiling point, such as the solvent and thelike, were distilled away. The obtained residue was purified by silicagel column chromatography (eluent: ethyl acetate/hexane=1/10 (volumeratio)) to give 2-ethoxycarbonyl-7-oxabicyclo[2.2.1]hept-5-ene as amixture of exo form:endo form=7:3 (1.75 g, 10.4 mmol, yield 52.0%).

IR(neat, cm⁻¹): 2986, 1734, 1450, 1369, 1340, 1315, 1277, 1192, 1095,1047, 1024.

¹H-NMR (250 MHz, CDCl₃, TMS, ppm) δ: exo form: 6.42-6.32 (2H, m), 5.19(1H, s), 5.08 (1H, d, J=4.5 Hz), 4.19 (2H, q, J=7.2 Hz), 2.45-2.40 (1H,m), 2.22-2.19 (1H, m), 1.68-1.48 (1H, m), 1.28 (3H, t, J=7.2 Hz) endoform: 6.46-6.43 (1H, m), 6.25-6.22 (1H, m), 5.18-5.16 (1H, m), 5.03-5.01(1H, m), 4.10 (2H, q, J=7.2 Hz), 3.18-3.05 (1H, m), 2.18-2.02 (1H, M),1.68-1.52 (1H, m), 1.24 (3H, t, J=7.2 Hz).

EIMS m/z: 139[(M-C₂H₅)⁺], 123[(M-C₂H₅O)⁺], 99, 68, 55, 39, 28.

HRMS calcd for C₉H₁₂O₃(M⁺): 168.0786, Found m/z=168.0771.

Reference Example 2 Synthesis of ethyl5-hydroxy-1,3-cyclohexadiene-1-carboxylate

To a solution (10.72 ml, 1.0 mol/l, 10.72 mmol) of lithiumhexamethyldisilazide in tetrahydrofuran was added tetrahydrofuran (60ml), and the mixture was cooled to −78° C. To this solution was addeddropwise a solution of 2-15 ethoxycarbonyl-7-oxabicyclo[2.2.1]hept-5-ene(a mixture of exo form:endo form=7:3, 1.64 g, 9.75 mmol, obtained inReference Example 1) in tetrahydrofuran (12 ml). After the dropwiseaddition, the mixture was heated to 0° C. and stirred for 1.5 h. To thisreaction mixture was added saturated aqueous ammonium chloride solution(50 ml), and the mixture was extracted with chloroform (100 ml). Theorganic layer was partitioned, washed with saturated brine (20 ml), anddried over anhydrous sodium sulfate. The components having a low boilingpoint, such as the solvent and the like, were distilled away. Theobtained residue was purified by silica gel column chromatography(eluent: ethyl acetate/hexane=1/5 (volume ratio)) to give ethyl5-hydroxy-1,3-cyclohexadiene-1-carboxylate (1.52 g, 9.06 mmol, yield93.9).

IR(neat, cm⁻¹): 3412, 3045, 2982, 2937, 2906, 1705, 1641, 1577, 1446,1402, 1367, 1255, 1203, 1099, 1059, 1026.

¹H-NMR (250 MHz, CDCl₃, TMS, ppm) δ: 7.12-7.03 (1H, m), 6.31-6.18 (2H,m), 4.45-4.32 (1H, m), 4.23 (2H, q, J=7.2 Hz), 3.00-2.85 (1H, m),2.71-2.54 (1H, m), 1.58 (1H, s), 1.31 (3H, t, J=7.2 Hz).

Reference Example 3 Synthesis of ethyl(1β,5α,6β)-5-hydroxy-7-oxabicyclo[4.1.0]hept-2-ene-3-carboxylate

Ethyl 5-hydroxy-1,3-cyclohexadiene-1-carboxylate (2.84 g, 16.88 mmol),obtained according to the method of Reference Example 2, was dissolvedin dichloromethane (20 ml), and sodium hydrogen carbonate (7.09 g, 84.4mmol) was added. The mixture was cooled to 0° C. and to this solutionwas added dropwise a solution of 80% m-chloroperbenzoic acid (4.00 g,18.57 mmol) in dichloromethane (30 ml). After the dropwise addition, themixture was heated to room temperature and stirred for 12 h. The solidin the reaction mixture was filtered off, and the filtrate was washedwith 5% aqueous sodium sulfite solution (30 ml) and saturated brine (20ml), and dried over anhydrous sodium sulfate. The components having alow boiling point, such as the solvent and the like, were distilledaway. The obtained residue was purified by silica gel columnchromatography (eluent: ethyl acetate/hexane=1/5 (volume ratio)) to giveethyl (1β,5α,6β)-5-hydroxy-7-oxabicyclo[4.1.0]hept-2-ene-3-carboxylate(2.61 g, 14.17 mmol, yield 83.9%).

IR(neat, cm⁻¹): 3435, 2984, 2908, 1712, 1645, 1373, 1251, 1188, 1091,1057.

¹H-NMR (250 MHz, CDCl₃, TMS, ppm) δ: 7.03-7.00 (1H, m), 4.21 (2H, q,J=7.2 Hz), 4.22-4.06 (1H, m), 3.69-3.61 (1H, m), 3.56-3.45 (1H, m),3.01-2.83 (1H, m), 2.00 (1H, s), 1.29 (3H, t, J=7.2 Hz).

EIMS m/z: 166[(M-2H₂O)⁺], 155[(M-C₂H₅)⁺], 138[(M-C₂H₅—H₂O)⁺],110[(M-CO₂C₂H₅)⁺], 82, 53.

HRMS: calcd for C₉H₁₂O₄(M⁺) 184.0735, Found m/z=184.0726.

Example 1 Synthesis of ethyl(3β,4α,5α)-3-benzhydrylamino-4,5-dihydroxy-1-cyclohexene-1-carboxylate

Ethyl (1β,5α,6β)-5-hydroxy-7-oxabicyclo[4.1-O]hept-2-ene-3-carboxylate(245 mg, 1.33 mmol) obtained in Reference Example 3 was dissolved intetrahydrofuran (0.5 ml), and benzhydrylamine (365 mg, 2.00 mmol) wasadded. The mixture was stirred at 65° C. for 2 days. The reactionmixture was cooled to room temperature, and the components having a lowboiling point, such as the solvent and the like, were distilled away.The obtained residue was purified by silica gel column chromatography(eluent: ethyl acetate/hexane=1/1 (volume ratio)) to give ethyl(3β,4α,5α)-3-benzhydrylamino-4,5-dihydroxy-1-cyclohexene-1-carboxylate(457 mg, 1.24 mmol, yield 93.5%).

IR(neat, cm⁻¹): 3437, 3061, 3028, 2984, 2906, 1709, 1649, 1452, 1367,1265, 1076, 1047.

¹H-NMR (250 MHz, CDCl₃, TMS, ppm) δ: 7.46-7.22 (10H, m), 6.99-6.98 (1H,m), 5.16 (1H, s), 4.20 (2H, q, J=7.2 Hz), 3.53-3.38 (2H, m), 2.55-2.54(2H, m), 1.29 (3H, t, J=7.2 Hz).

EIMS m/z: 367(M⁺), 307[(M-C₂H₄O₂)⁺], 200[(M-CHPh₂)⁺], 167.

HRMS: calcd for C₂₂H₂₅NO₄(M⁺) 367.1784, Found m/z=367.1785.

Example 2 Synthesis of ethyl(1α,5α,6α)-7-diphenylmethyl-5-methanesulfonyloxy-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylate

Ethyl (3β,4α,5α)-3-benzhydrylamino-4,5-dihydroxy-1-25cyclohexene-1-carboxylate (110 mg, 0.299 mmol) obtained in Example 1 wasdissolved in tetrahydrofuran (2 ml), and triethylamine (1 ml) was added.The mixture was stirred at room temperature for 5 min and cooled to 0°C. To this solution was added dropwise methanesulfonyl chloride (103 mg,0.687 mmol), and after the dropwise addition, the mixture was heated to65° C. and stirred for 24 h. The reaction mixture was cooled to roomtemperature and concentrated. The residue was diluted withdichloromethane (20 ml), washed with saturated aqueous sodium hydrogencarbonate solution (20 ml) and saturated brine (10 ml), and dried overanhydrous sodium sulfate. The components having a low boiling point,such as the solvent and the like, were distilled away. The obtainedresidue was purified by silica gel column chromatography (eluent: ethylacetate/hexane=1/3 (volume ratio)) to give ethyl(1α,5α,6α)-7-diphenylmethyl-5-methanesulfonyloxy-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylate(71.3 mg, 0.167 mmol, yield 55.7%).

IR(neat, cm⁻¹): 3022, 1705, 1359, 1267, 1217, 1172, 1095.

¹H-NMR (250 MHz, CDCl₃, TMS, ppm) δ: 7.23-7.19 (11H, m), 5.32-5.28 (1H,m), 4.21 (2H, q, J=7.2 Hz), 3.83 (1H, s), 3.09-2.98 (1H, m), 2.97 (3H,s), 2.68-2.55 (2H, m), 2.41-2.32 (1H, m), 1.31 (3H, t, J=7.2 Hz).

EIMS m/z: 331[(M-O₃SCH₃)⁺], 167.

HRMS calcd for C₂₃H₂₅NO₅S(M⁺): 427.1454, Found m/z=427.1452.

Example 3 Synthesis of ethyl(1α,5α,6α)-7-diphenylmethyl-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate

Ethyl(1α,5α,6α)-7-diphenylmethyl-5-methanesulfonyloxy-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylate(235 mg, 0.55 mmol) obtained according to the method of Example 2,3-pentanol (6 ml) and dichloromethane (2 ml) were mixed and dissolved.To this solution was added boron trifluoride etherate (390 mg, 2.45mmol) at room temperature, and the mixture was stirred at roomtemperature for 3 h. To this reaction mixture was added triethylamine(556 mg, 5.49 mmol) at room temperature, and the mixture was stirred atroom temperature for 1 more h. The reaction mixture was concentrated,and the residue was diluted with diethyl ether (20 ml), washed withsaturated aqueous sodium hydrogen carbonate solution (10 ml) andsaturated brine (5 ml), and dried over anhydrous sodium sulfate. Thecomponents having a low boiling point, such as the solvent and the like,were distilled away. The obtained residue was purified by silica gelcolumn chromatography (eluent: ethyl acetate/hexane=1/3 (volume ratio))to give ethyl(1α,5α,6α)-7-diphenylmethyl-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate(197 mg, 0.47 mmol, yield 85.6%).

IR(neat, cm⁻¹): 2968, 2934, 2876, 1714, 1660, 1493, 1302, 1248, 1080,1060.

¹H-NMR (250 MHz, CDCl₃, TMS, ppm) δ: 7.41-7.21 (10H, m), 6.81-6.75 (1H,m), 4.19 (2H, q, J=7.2 Hz), 4.10-4.01 (1H, m), 3.71 (1H, s), 3.17-3.07(1H, m), 2.76-2.65 (1H, m), 2.64-2.48 (1H, m), 2.18-2.08 (1H, m),2.00-1.91 (1H, m), 1.49-1.34 (4H, m), 1.31 (3H, t, J=7.2 Hz), 0.86-0.78(6H, m).

EIMS m/z: 419(M⁺), 346[(M-CO₂C₂H₅)⁺], 305, 167.

HRMS: calcd for C₂₇H₃₃NO₃(M⁺): 419.2461, Found m/z=419.2464.

Example 4 Synthesis of ethyl(1α,5α,6α)-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate

Ethyl(1α,5α,6α)-7-diphenylmethyl-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate(17 mg, 0.0405 mmol) obtained in Example 3 and 10% palladium-carbon (17mg) were placed in a flask and the mixture was cooled to 0° C. Theretowas added formic acid (4.4% methanol solution, 1 ml) cooled to 0° C. andthe mixture was stirred at 0° C. for 3 h. The reaction mixture wasfiltrated and the filtrate was concentrated. The residue was dilutedwith dichloromethane (10 ml), washed with saturated aqueous sodiumhydrogen carbonate solution (10 ml) and saturated brine (5 ml), anddried over anhydrous sodium sulfate. The components having a low boilingpoint, such as the solvent and the like, were distilled away. Theobtained residue was purified by silica gel column chromatography(eluent: ethyl acetate/hexane=1/4→5/1 (volume ratio)) to give ethyl(1α,5α,6α)-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate(4.3 mg, 0.0169 mmol, yield 41.7%), and the starting material: ethyl(1α,5α,6α)-7-diphenylmethyl-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate(6.75 mg) was recovered (0.0161 mmol, recovery yield 39.7%).

IR(neat, cm⁻¹): 2962, 2926, 2854, 1716, 1462, 1381, 1251, 1130, 1084,1057.

¹H-NMR (500 MHz, CDCl₃, TMS, ppm) δ: 6.79-6.78 (1H, m), 4.33-4.32 (1H,m), 4.18 (2H, q, J=7.2 Hz), 3.41-3.38 (1H, m), 2.84-2.80 (1H, m),2.64-2.60 (1H, m), 2.53-2.51 (1H, m), 2.43-2.42 (1H, m), 1.58-1.53 (1H,m), 1.27 (3H, t, J=7.2 Hz), 0.96 (3H, t, J=7.5 Hz), 0.91 (3H, t, J=7.5Hz).

EIMS m/z: 253(M⁺), 224[(M-C₂H₅)⁺], 208[(M-OC₂H₅)⁺], 182[(M-C₅H₁₁)⁺],166[(M-OC₅H₁₁)⁺], 154, 137, 110, 93.

HRMS calcd for C₁₄H₂₃NO₃(M⁺): 253.1678, Found m/z=253.1695.

Example 5 Synthesis of ethyl(3β,4α,5α)-3-benzylamino-4,5-dihydroxy-1-cyclohexene-1-carboxylate

Ethyl (1β,5α,60)-5-hydroxy-7-oxabicyclo[4.1.0]hept-2-ene-3-carboxylate(1.00 g, 5.42 mmol) obtained in Reference Example 3 was dissolved intetrahydrofuran (1 ml), and benzylamine (0.652 g, 5.96 mmol) was added.The mixture was stirred at 50° C. for 18 h and the reaction mixture wascooled to room temperature. The components having a low boiling point,such as the solvent and the like, were distilled away. The obtainedresidue was purified by silica gel column chromatography (eluent: ethylacetate/hexane=5/1 (volume ratio)) to give ethyl(3β,4α,5α)-3-benzylamino-4,5-dihydroxy-1-cyclohexene-1-carboxylate (1.49g, 5.10 mmol, yield 94.1%).

IR(neat, cm⁻¹): 3402, 2982, 2905, 1709, 1651, 1454, 1367, 1255, 1080.

¹H-NMR (250 MHz, CDCl₃, TMS, ppm) δ: 7.39-7.26 (5H, m), 6.96 (1H, s),4.29-4.21 (1H, m), 4.21 (2H, q, J=7.2 Hz), 3.93 (2H, dd, J=53, 13 Hz),3.48 (1H, s), 3.52-3.40 (1H, m), 2.82-2.45 (2H, m), 1.29 (3H, t, J=7.2Hz).

EIMS m/z: 291(M⁺), 255[(M-2H₂O)⁺], 231, 91.

HRMS calcd for C₁₆H₂₁NO₄(M⁺): 291.1471, Found m/z=291.1457.

Example 6 Synthesis of ethyl(3β,4α,5α)-3-{N-(tert-butoxycarbonyl)-N-benzylamino}-4,5-dihydroxy-1-cyclohexene-1-carboxylate

Ethyl (3β,4α,5α)-3-benzylamino-4,5-dihydroxy-1-cyclohexene-1-carboxylate(1.48 g, 5.07 mmol) obtained in Example 5 was dissolved in acetonitrile(10 ml), and di-tert-butyl dicarbonate (1.22 g, 5.58 mmol) was added.The mixture was stirred at room temperature for 1.5 h and, after thecompletion of the reaction, the components having a low boiling point,such as the solvent and the like, were distilled away. The obtainedresidue was purified by silica gel column chromatography (eluent: ethylacetate/hexane=1/3 (volume ratio)) to give ethyl(3β,4α,5α)-3-{N-(tert-butoxycarbonyl)-N-benzylamino}-4,5-dihydroxy-1-cyclohexene-1-carboxylate(1.75 g, 4.47 mmol, yield 88.2%).

IR(neat, cm⁻¹): 3441, 3011, 2980, 2934, 1693, 1454, 1410, 1367, 1253,1165, 1084.

EIMS m/z: 391(M⁺), 335[(M-C₄H₈)⁺], 290[(M-C₄H₉CO₂)⁺], 231, 91.

HRMS calcd for C₂₁H₂₉NO₆(M⁺): 391.1995, Found m/z=391.1987.

Example 7 Synthesis of ethyl(3β,4α,5α)-3-{N-(tert-butoxycarbonyl)-N-benzylamino}-4,5-dimethanesulfonyloxy-1-cyclohexene-1-carboxylate

Ethyl(3β,4α,5α)-3-{N-(tert-butoxycarbonyl)-N-benzylamino}-4,5-dihydroxy-1-cyclohexene-1-carboxylate(1.73 g, 4.42 mmol) obtained in Example 6 was dissolved in methylenechloride (20 ml), and triethylamine (1.12 g, 11.05 mmol) was added. Themixture was stirred at room temperature for 5 min and this reactionmixture was cooled to 0° C. Methanesulfonyl chloride (1.11 g, 9.72 mmol)was added dropwise over 5 min and, after the dropwise addition, themixture was stirred at room temperature for 1.5 h. The components havinga low boiling point, such as the solvent and the like, were distilledaway. The obtained residue was purified by silica gel columnchromatography (eluent: ethyl acetate/hexane=1/5 (volume ratio)) to giveethyl(3β,4α,5α)-3-{N-(tert-butoxycarbonyl)-N-benzylamino}-4,5-dimethanesulfonyloxy-1-cyclohexene-1-carboxylate(2.41 g, 4.40 mmol, yield 99.6%).

IR(neat, cm⁻¹): 2980, 2939, 1701, 1454, 1419, 1359, 1246, 1176, 1091,1057, 1005.

EIMS m/z: 491[(M-C₄H₈)⁺], 381, 244, 150, 106, 91.

HRMS calcd for C₁₉H₂₅NO₁₀S₂[(M-C₄H₈)⁺]: 491.0920, Found m/z=491.0901.

Example 8 Synthesis of ethyl(3β,4α,5α)-3-benzylamino-4,5-dimethanesulfonyloxy-1-cyclohexene-1-carboxylate

Ethyl(3β,4α,5α)-3-{N-(tert-butoxycarbonyl)-N-benzylamino}-4,5-dimethanesulfonyloxy-1-cyclohexene-1-carboxylate(2.11 g, 3.85 mmol) obtained according to the method of Example 7 wasdissolved in methylene chloride (66 ml), 20 and trifluoroacetic acid(4.4 g, 38.5 mmol) was added. The mixture was stirred at roomtemperature for 18 h. The reaction mixture was washed with saturatedaqueous sodium hydrogen carbonate solution (50 ml) and saturated brine(20 ml), and dried over anhydrous sodium sulfate. The components havinga low boiling point, such as the solvent and the like, were distilledaway. The obtained residue was purified by silica gel columnchromatography (eluent: ethyl acetate/hexane=1/5 (volume ratio)) to giveethyl(3β,4α,5α)-3-benzylamino-4,5-dimethanesulfonyloxy-1-cyclohexene-1-carboxylate(1.65 g, 3.69 mmol, yield 96.0%).

IR(neat, cm⁻¹): 3028, 2984, 2939, 2361, 1712, 1653, 1454, 1359, 1249,1176, 1095, 1045, 1003.

¹H-NMR (250 MHz, CDCl₃, TMS, ppm) δ: 7.38-7.25 (5H, m), 6.87-6.79 (1H,m), 5.28-5.18 (1H, m), 4.89-4.79 (1H, m), 4.22 (2H, q, J=7.2 Hz), 3.92(2H, dd, J=22.5, 14.2 Hz), 3.81-3.70 (1H, m), 3.12 (1H, s), 3.19 (1H,s), 2.88-2.78 (2H, m), 1.30 (3H, t, J=7.2 Hz).

Example 9 Synthesis of ethyl(1α,5α,6α)-7-benzyl-5-methanesulfonyloxy-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylate

Ethyl (3β,4α,5α)-3-benzylamino-4,5-dimethanesulfonyloxy-1-cyclohexene-1-carboxylate(0.278 g, 0.62 mmol) obtained in Example 8 was dissolved intetrahydrofuran (1 ml), and triethylamine (1 ml) was added. The mixturewas stirred at 50° C. for 2 days. The reaction mixture was cooled toroom temperature. The components having a low boiling point, such as thesolvent and the like, were distilled away. The obtained residue waspurified by silica gel column chromatography (eluent: ethylacetate/hexane=1/3 (volume ratio)) to give ethyl(3α,5α,5α)-7-benzyl-5-methanesulfonyloxy-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylate(0.124 g, 0.352 mmol, yield 56.7%).

IR(neat, cm⁻¹): 1707, 1358, 1265, 1209, 1172, 1095.

¹H-NMR (250 MHz, CDCl₃, TMS, ppm) δ: 7.39-7.20 (6H, m), 5.47-5.37 (1H,m), 4.19 (2H, q, J=7.2 Hz), 3.59 (2H, dd, J=75, 14 Hz), 3.00 (1H, s),3.05-2.89 (1H, m), 2.65-2.38 (2H, m), 2.34-2.22 (1H, m), 1.28 (3H, t,J=7.2 Hz).

EIMS m/z: 351(M⁺), 256[(M-O₃SCH₃)⁺], 164, 91.

HRMS calcd for C₁₇H₂₁NO5S(M⁺): 351.1141, Found m/z=351.1110.

Example 10 Synthesis of ethyl(1α,5α,6α)-7-benzyl-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate

Ethyl(1α,5α,6α)-7-benzyl-5-methanesulfonyloxy-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylate(50 mg, 0.142 mol) obtained in Example 9 was dissolved in 3-pentanol (1ml), and boron trifluoride etherate (22.2 mg, 0.156 mmol) was added atroom temperature. The mixture was stirred at 65° C. for 3 h. Thereaction mixture was cooled to room temperature. Triethylamine (21.6 mg,0.213 mmol) was added and the mixture was stirred at room temperaturefor 1 h. The reaction mixture was concentrated, and the residue wasdiluted with diethyl ether (10 ml), washed with saturated aqueous sodiumhydrogen carbonate solution (5 ml) and saturated brine (3 ml), and driedover anhydrous sodium sulfate. The components having a low boilingpoint, such as the solvent and the like, were distilled away. Theobtained residue was purified by silica gel column chromatography(eluent: ethyl acetate/hexane=1/3 (volume ratio)) to give ethyl(1α,5α,6α)-7-benzyl-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate(42.8 mg, 0.125 mmol, yield 87.7%).

IR(neat, cm⁻¹): 2968, 2934, 2876, 1714, 1454, 1369, 1302, 1248, 1080,1059.

¹H-NMR (250 MHz, CDCl₃, TMS, ppm) δ: 7.33-7.28 (5H, m), 6.78-6.77 (1H,m), 4.30-4.20 (1H, m), 4.16 (2H, q, J=7.2 Hz), 3.58 (1H, s), 3.40-3.21(1H, m), 2.83-2.66 (1H, m), 2.65-2.48 (1H, m), 2.11-2.00 (1H, m),2.00-1.88 (1H, m), 1.68-1.43 (4H, m), 1.25 (3H, t, J=7.2 Hz), 0.93 (3H,t, J=7.4 Hz), 0.89 (3H, t, J=7.4 Hz).

EIMS m/z: 343(M⁺), 314[(M-C₂H₅)⁺], 272[(M-C₅H₁₁)⁺], 256, 200, 91

HRMS calcd for C₂₁H₂₉NO₃(M⁺): 343.2148, Found m/z=343.2147.

Example 11 Synthesis of ethyl(1α,5α,6α)-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate

Ethyl(1α,5α,6α)-7-benzyl-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate(19 mg, 0.055 mmol) obtained in Example 10 and 10% palladium-carbon (19mg) were placed in a flask and formic acid (4.4% methanol solution, 1ml) was added at room temperature. The mixture was stirred at roomtemperature for 10 min. The reaction mixture was filtrated and thefiltrate was concentrated. The residue was diluted with dichloromethane(10 ml), washed with saturated aqueous sodium hydrogen carbonatesolution (10 ml) and saturated brine (5 ml), and dried over anhydroussodium sulfate. The components having a low boiling point, such as thesolvent and the like, were distilled away. The obtained residue waspurified by silica gel column chromatography (eluent:ethylacetate/hexane=1/4→5/1 (volume ratio)) to give ethyl(1α,5α,6α)-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate(8.1 mg, 0.0319 mmol, yield 58.0%).

IR(neat, cm⁻¹): 2962, 2926, 2854, 1716, 1462, 1381, 1251, 1130, 1084,1057.

¹H-NMR (500 MHz, CDCl₃, TMS, ppm) δ: 6.79-6.78 (1H, m), 4.33-4.32 (1H,m), 4.18 (2H, q, J=7.2 Hz), 3.41-3.38 (1H, m), 2.84-2.80 (1H, m),2.64-2.60 (1H, m), 2.53-2.51 (1H, m), 2.43-2.42 (1H, m), 1.58-1.53 (1H,m), 1.27 (3H, t, J=7.2 Hz), 0.96 (3H, t, J=7.5 Hz), 0.91 (3H, t, J=7.5Hz).

EIMS m/z: 253(M⁺), 224[(M-C₂H₅)⁺], 208[(M-OC₂H₅)⁺], 182[(M-C₅H₁₁)⁺],166[(M-OC₅H₁₁)⁺], 154, 137, 110, 93.

HRMS calcd for C₁₄H₂₃NO₃(M⁺): 253.1678, Found m/z=253.1695.

The α and β show the relative configuration of the substituents on thering. The relative configuration of Example compounds are shown in thefollowing, where α is conveniently placed on the upper side of the sheetand β on the lower side of the sheet, but these structural formulas donot represent the absolute configuration. Dpm means diphenylmethyl, Bzlmeans benzyl, Boc means tert-butoxycarbonyl, Ms means methanesulfonyland Et means ethyl.

Industrial Applicability

According to the present invention,7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester such as ethyl(1α,5α,6α)-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylateuseful as a synthetic intermediate for GS4104 being developed as ananti-influenza drug can be produced economically, industriallyadvantageously and efficiently in a large amount. The epoxide (I), whichis a starting material in the method of the present invention,-can besynthesized from an economical starting material. Therefore, accordingto the method of the present invention,7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester can be producedfrom an economical starting material, without using an expensivestarting material. The method of the present invention is suitable forproducing 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid esterindustrially in a large amount.

This application is based on a patent application no. 11-312616 filed inJapan, the contents of which are hereby incorporated by reference.

What is claimed is:
 1. A production method of a7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester of the formula(VII)

wherein R¹ is an alkyl group optionally having substituents, acycloalkyl group optionally having substituents, an aryl groupoptionally having substituents or an aralkyl group optionally havingsubstituents and R³ is an alkyl group optionally having substituents, acycloalkyl group optionally having substituents, an alkenyl groupoptionally having substituents, an aryl group optionally havingsubstituents or an aralkyl group optionally having substituents, whichcomprises the steps of (A) reacting a5-hydroxy-7-oxabicyclo[4.1.0]hept-2-ene-3-carboxylic acid ester of theformula (I)

wherein R¹ is as defined above, with an amine of the formula (II)R²NH₂  (II) wherein R² is a hydrogen atom, an alkyl group optionallyhaving substituents, a cycloalkyl group optionally having substituents,an alkenyl group optionally having substituents, an aryl groupoptionally having substituents or an aralkyl group optionally havingsubstituents, to give a 3-amino-4,5-dihydroxy-1-cyclohexene-1-carboxylicacid ester of the formula (III)

wherein R¹ and R² are as defined above, (B) reacting the obtained3-amino-4,5-dihydroxy-1-cyclohexene-1-carboxylic acid ester with asulfonylating agent in the presence of a base to give a5-sulfonyloxy-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylic acid ester ofthe formula (IV)

wherein R¹ and R² are as defined above and A is an organic sulfonylgroup, (C) reacting the obtained5-sulfonyloxy-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylic acid ester withan alcohol of the formula (V) R³OH  (V) wherein R³ is as defined above,in the presence of a Lewis acid to give a5-oxy-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester of theformula (VI)

wherein R¹, R² and R³ are as defined above, and (D) when R² is an alkylgroup optionally having substituents, a cycloalkyl group optionallyhaving substituents, an alkenyl group optionally having substituents, anaryl group optionally having substituents or an aralkyl group optionallyhaving substituents, eliminating the 7-position substituent R² of theobtained 5-oxy-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester. 2.A production method of a 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acidester of the formula (VII)

wherein R¹ is an alkyl group optionally having substituents, acycloalkyl group optionally having substituents, an aryl groupoptionally having substituents or an aralkyl group optionally havingsubstituents and R³ is an alkyl group optionally having substituents, acycloalkyl group optionally having substituents, an alkenyl groupoptionally having substituents, an aryl group optionally havingsubstituents or an aralkyl group optionally having substituents, whichcomprises the steps of (A) reacting a5-hydroxy-7-oxabicyclo[4.1.0]hept-2-ene-3-carboxylic acid ester of theformula (I)

wherein R¹ is as defined above, with an amine of the formula (II)R²NH₂  (II) wherein R² is a hydrogen atom, an alkyl group optionallyhaving substituents, a cycloalkyl group optionally having substituents,an alkenyl group optionally having substituents, an aryl groupoptionally having substituents or an aralkyl group optionally havingsubstituents, to give a 3-amino-4,5-dihydroxy-1-cyclohexene-1-carboxylicacid ester of the formula (III)

wherein R¹ and R² are as defined above, (B) protecting an amino group ofthe obtained 3-amino-4,5-dihydroxy-1-cyclohexene-1-carboxylic acid esterto give a 3-amino-4,5-dihydroxy-1-cyclohexene-1-carboxylic acid ester ofthe formula (VIII)

wherein R¹ and R² are as defined above and R⁴ is an amino-protectinggroup, (C) reacting the obtained3-amino-4,5-dihydroxy-1-cyclohexene-1-carboxylic acid ester with asulfonylating agent in the presence of a base to give a3-amino-4,5-disulfonyloxy-1-cyclohexene-1-carboxylic acid ester of theformula (IX)

wherein R¹, R² and R⁴ are as defined above and A is an organic sulfonylgroup, (D) removing the amino-protecting group from the obtained3-amino-4,5-disulfonyloxy-1-cyclohexene-1-carboxylic acid ester to givea 3-amino-4,5-disulfonyloxy-1-cyclohexene-1-carboxylic acid ester of theformula (X)

wherein R¹, R² and A are as defined above, (E) reacting the obtained3-amino-4,5-disulfonyloxy-1-cyclohexene-1-carboxylic acid ester with abase to give a 5-sulfonyloxy-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylicacid ester of the formula (IV)

wherein R¹, R² and A are as defined above, (F) reacting the obtained5-sulfonyloxy-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylic acid ester withan alcohol of the formula (V) R³OH  (V) wherein R³ is as defined above,in the presence of a Lewis acid to give a5-oxy-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester of theformula (VI)

wherein R¹, R² and R³ are as defined above, and (G) when R² is an alkylgroup optionally having substituents, a cycloalkyl group optionallyhaving substituents, an alkenyl group optionally having substituents, anaryl group optionally having substituents or an aralkyl group optionallyhaving substituents, eliminating the 7-position substituent R² from theobtained 5-oxy-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester. 3.A production method of a 7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acidester the formula (VII)

wherein R¹ is an alkyl group optionally having substituents, acycloalkyl group optionally having substituents, an aryl groupoptionally having substituents or an aralkyl group optionally havingsubstituents and R³ is an alkyl group optionally having substituents, acycloalkyl group optionally having substituents, an alkenyl groupoptionally having substituents, an aryl group optionally havingsubstituents or an aralkyl group optionally having substituents, whichcomprises eliminating a 7-position substituent R²′, from a5-oxy-7-azabicyclo[4.1.0]hept-3-carboxylic acid ester of the formula(VI′)

wherein R²′, is an alkyl group optionally having substituents, acycloalkyl group optionally having substituents, an alkenyl groupoptionally having substituents, an aryl group optionally havingsubstituents, an alkenyl group optionally having substituents, and R¹and R³ are as defined above.
 4. A production method of a5-oxy-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylic acid ester of theformula (VI)

wherein R¹ is an alkyl group optionally having substituents, acycloalkyl group optionally having substituents, an aryl groupoptionally having substituents or an aralkyl group optionally havingsubstituents, R² is a hydrogen atom, an alkyl group optionally havingsubstituents, a cycloalkyl group optionally having substituents, analkenyl group optionally having substituents, an aryl group optionallyhaving substituents or an aralkyl group optionally having substituentsand R³ is an alkyl group optionally having substituents, a cycloalkylgroup optionally having substituents, an alkenyl group optionally havingsubstituents, an aryl group optionally having substituents or an aralkylgroup optionally having substituents, which comprises reacting a5-sulfonyloxy-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylic acid ester ofthe formula (IV)

wherein A is an organic sulfonyl group, and R¹ and R² are as definedabove, with an alcohol of the formula (V) R³OH  (V) wherein R³ is asdefined above, in the presence of a Lewis acid.
 5. A production methodof a 5-sulfonyloxy-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylic acid esterof the formula (IV)

wherein R¹ is an alkyl group optionally having substituents, acycloalkyl group optionally having substituents, an aryl groupoptionally having substituents or an aralkyl group optionally havingsubstituents and R² is a hydrogen atom, an alkyl group optionally havingsubstituents, a cycloalkyl group optionally having substituents, analkenyl group optionally having substituents, an aryl group optionallyhaving substituents or an aralkyl group optionally having substituentsand A is an organic sulfonyl group, which comprises reacting a3-amino-4,5-dihydroxy-1-cyclohexene-1-carboxylic acid ester of theformula (III)

wherein R¹ and R² are as defined above, with a sulfonylating agent inthe presence of a base.
 6. A production method of a5-sulfonyloxy-7-azabicyclo-[4.1.0]hept-2-ene-3-carboxylic acid ester ofthe formula (IV)

wherein R¹ is an alkyl group optionally having substituents, acycloalkyl group optionally having substituents, an aryl groupoptionally having substituents or an aralkyl group optionally havingsubstituents, R² is a hydrogen atom, an alkyl group optionally havingsubstituents, a cycloalkyl group optionally having substituents, analkenyl group optionally having substituents, an aryl group optionallyhaving substituents or an aralkyl group optionally having substituentsand A is an organic sulfonyl group, which comprises reacting a3-amino-4,5-disulfonyloxy-1-cyclohexene-1-carboxylic acid ester of theformula (X)

wherein R¹, R² and A are as defined above, with a base.
 7. A productionmethod of a 5-sulfonyloxy-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylicacid ester of the formula (IV)

wherein R¹ is an alkyl group optionally having substituents, acycloalkyl group optionally having substituents, an aryl groupoptionally having substituents or an aralkyl group optionally havingsubstituents, R² is a hydrogen atom, an alkyl group optionally havingsubstituents, a cycloalkyl group optionally having substituents, analkenyl group optionally having substituents, an aryl group optionallyhaving substituents or an aralkyl group optionally having substituents,and A is an organic sulfonyl group, which comprises (A) protecting anamino group of a 3-amino-4,5-dihydroxy-1-cyclohexene-1-carboxylic acidester of the formula (III)

wherein R¹ and R² are as defined above, to give a3-amino-4,5-dihydroxy-1-cyclohexene-1-carboxylic acid ester of theformula (VIII)

wherein R¹ and R² are as defined above, and R⁴ is an amino-protectinggroup, (B) reacting the obtained3-amino-4,5-dihydroxy-1-cyclohexene-1-carboxylic acid ester with asulfonylating agent in the presence of a base to give a3-amino-4,5-disulfonyloxy-1-cyclohexene-1-carboxylic acid ester of theformula

wherein R¹, R², R⁴ and A are as defined above, (C) removing theamino-protecting group of the obtained3-amino-4,5-disulfonyloxy-1-cyclohexene-1-carboxylic acid ester to givea 3-amino-4,5-disulfonyloxy-1-cyclohexene-1-carboxylic acid ester of theformula (X)

wherein R¹ R² and A are as defined above, and (D) reacting the obtained3-amino-4,5-disulfonyloxy-1-cyclohexene-1-carboxylic acid ester with abase.
 8. A production method of a3-amino-4,5-dihydroxy-1-cyclohexene-1-carboxylic acid ester of theformula (III)

wherein R¹ is an alkyl group optionally having substituents, acycloalkyl group optionally having substituents, an aryl groupoptionally having substituents or an aralkyl group optionally havingsubstituents and R² is a hydrogen atom, an alkyl group optionally havingsubstituents, a cycloalkyl group optionally having substituents, analkenyl group optionally having substituents, an aryl group optionallyhaving substituents or an aralkyl group optionally having substituents,which comprises reacting a5-hydroxy-7-oxabicyclo[4.1.0]hept-2-ene-3-carboxylic acid ester of theformula (I)

wherein R¹ is as defined above, with an amine of the formula (II)R²NH₂  (II) wherein R² is as defined above.